Place of chemotherapy in the management of brain metastases

Place of chemotherapy in the
management of brain metastases
Pr Antoine Carpentier, hôpital Avicenne
42-yr old nurse
March 2011: Headaches
MRI: (16/3/2011) : 2 cerebellar lesions
CT scan + PET FDG: one mediastinal adenopathy
echo-endoscopy biospy:
lung adenocarcinoma
Mutated EGFR
⇒ sensitivity to erlotinib/gefitinib
Oncological Managment of brain metastases:
2 cases
Metastase eligible for surgical
resection or radiosurgery
#10%
Metastase non eligible for surgical
resection or radiosurgery
#90%
Surgical resection or Radiosurgery ?
• Surgery if
• size> 35mm
• If histology required
• Radiosurgery if
• Size < 30mm
• Up to 3 (or 4) metastases
Managment of brain metastases:
2 cases
Metastase eligible for surgical
resection or radiosurgery
Metastase non eligible for surgical
resection or radiosurgery
Whole brain radiotherapy (WBRT)
standard protocol =
30 Gy in 10 fractions /12 days
radiological response rate: # 30% in NSCLC
# 50% in breast cancer
Metha, 2003 ; Stea, 2006 ; Suh, 2006
La chimiothérapie peut elle être une
alternative?
accès de la molécule à la métastase:
« La BHE est le problème »
BHE est elle vraiment fonctionnelle?
Structure of Blood Brain Barrier
1. Endothelium
a. tight intercellular junctions
b. relative lack of vesicular transport
2. Pericytes with smooth muscle- like properties
3. Astroglial process ( >95% of the luminal vessel surface)
Deeken et al. Clin Cancer Res, 2007.
BBB composition
Protein components:
– Claudin & Occludin heterodimer (no occludin Breakdown of BBB)
– Junction Adhesion Molecules (Ig superfamily) : cell-to-cell
adhesion and leukocyte transmigration through BBB
– Accessory proteins (ZO-1, ZO-2, ZO-3, cingulin, MAGUKS )
Ballabh et al
Transports
• Diffusion : pour les petits composés (< 400 Da), apolaires et lipophiles
• Transports actifs : composés polaires et hydrophiles
• transporteurs d’efflux
Deeken et al. Clin Cancer Res, 2007.
Les transporteurs d’efflux
-La P-glycoprotéine (P-gp) encore appelée ABCB1, MDR1
- Multidrug Resistance-associated Proteins (MRP)
de la famille ABCC (MRP1 à MRP9)
- Breast Cancer Resistance Protein (BRCP), encore appelée ABCG2
- Les transporteurs d’anions (OAT) et de cations (OCT) organiques
Deeken et al. Clin Cancer Res, 2007.
Les transporteurs d’efflux
Unidirectional Drug Transport at the BBB
BBB
Blood
CSF
Pgp
Compound Efflux
Transporteurs et spécificités de
substrats
Les transporteurs d’efflux composant la BHE et les agents chimiothérapeutiques
Transporteur
P-glycoprotéine
Nom HUGO
Substrats
ABCB1
Doxorubicine, daunorubicine, docetaxel, épirubicine, idarubicine,
vinblastine, étoposide
MRP1
ABCC1
Etoposide, teniposide, daunorubicine, doxorubicine, épirubicine,
melphalan, vincristine, vinblastine
MRP2
ABCC2
Similaire au MRP1
MRP3
ABCC3
Similaire au MRP1
MRP4
ABCC4
Méthotrexate, 6-mercaptopurine, thioguianine
MRP5
ABCC5
6-mercaptopurine, thioguianine
MRP6
ABCC6
Actinomycine D, cisplatine, daunorubicine, doxorubicine, étoposide
BCRP
ABCG2
Mitoxantrone, méthotrexate, SN-38, topotecan, imatinib, erlotinib,
gefitinib
gène MDR1
Deeken et al. Clin Cancer Res, 2007.
Principales chimiothérapies passant la BHE
Alkylants
• Nitrosourées (BCNU, CCNU)
• Témozolomide
• Procarbazine
15-30%
20-30%
• Sels de Platine (Carboplatine, CisPlat) <5%
Autres
• Poison Fuseau mitotique (vincristine)
• Inhib Topo 2 (Etoposide)
• Capecitabine (Xeloda)
1%
1-5%
TKI and the blood-brain-barrier
CSF studies (mainly in tumoral meningitis) (Jackman 2006; Masuda 2011)
- CSF levels < 10% serum levels
- Erlotinib > Gefitinib?
- Pulsatile high dose regimen? (Grommes 2011)
PET studies in 2 pts: Erlotinib accumulation in brain metastases
(Weber, 2011)
Alterations of the BBB
- Tumor itself
- Radiation
- high blood pressure
- Trauma, Ischemia, Inflammation, Infection
Métastases cérébrales HER2+
89Zr-Herceptin immunoPET
Dijkers et al. Journal of Clinical Oncology, 2007
Clin K Res 2010
Augmentation de la perméabilité :
• Rapide avec une radiothérapie à
simple dose
(une fraction de 20 Gy)1
Perméabilité (×10-7 cm/s)
Radiothérapie Encéphalique in toto
Avant
• Retardée avec une radiothérapie à
dose fractionnée (une fraction de 2
Gy 5 fois/semaine durant 4
semaines)2
Perméabilité (×10-7 cm/s)
Temps après irradiation (h)
Jours après début d’irradiation
(1) Yuan et al. Brain Research, 2003
(2) Yuan et al. International Journal of Radiation Oncology, 2006
Drug delivery through the BBB
• [intracerebral injections ]
• Pharmaceutic disruption of the BBB :
– osmotic means (IV Mannitol)
– vasoactive substances such as RMP-7 (bradykinin agonist)
– blocking of active efflux transporters
– localized exposure to ultrasound
• transport systems:
– Carrier/ receptor-mediated transcytosis (for ex transferrin receptors)
– nanoparticles / liposomes
Chemotherapy and brain metastases
Non small cell Lung cancer
No previous chemotherapy
No previous radiotherapy
Auteurs
date
chimiothérapie
n
RR cérébrale
Thomas
1990
cisplatine
30
27%
Minotti
Crino
Franciosio
Fugita
Robinet
Cortes
Cortot
Barlesi
Bailon
1998
1999
1999
2000
2001
2003
2006
cisplatine + téniposide
cisplatine + gemcitabine
cisplatine + étoposide
cisplatine + ifosfamide + irinotecan
cisplatine + vinorelbine
cisplatine + Taxotère + vinorelbine/gemcitabine
cisplatine + TMZ
23
26
43
30
86
25
50
35%
41%
30%
50%
27%
38%
12%
2011
Cisplatine+Alimta
43
42%
2012
Carboplatine+Alimta
30
40%
platine + others
Brain metastases are chemosensitive
32%
RR
systémique
26%
37%
62%
35%
50%
12%
33%
Chemotherapy and brain metastases
Non small cell Lung cancer
No previous chemotherapy
No previous radiotherapy
RR
systémique
Auteurs
date
chimiothérapie
n
RR cérébrale
Thomas
1990
cisplatine
30
27%
Minotti
Crino
Franciosio
Fugita
Robinet
Cortes
Cortot
Barlesi
1998
1999
1999
2000
2001
2003
2006
cisplatine + téniposide
cisplatine + gemcitabine
cisplatine + étoposide
cisplatine + ifosfamide + irinotecan
cisplatine + vinorelbine
cisplatine + Taxotère + vinorelbine/gemcitabine
cisplatine + TMZ
23
26
43
30
86
25
50
35%
41%
30%
50%
27%
38%
12%
2011
Cisplatine+Alimta
43
42%
62%
35%
50%
12%
35%
32%
33%
Cisplatine + others
Same chemosensitivity for brain/lung lesions
26%
37%
Tyrosine kinase inhibitors (TKI)
NSCLC + Brain metastases
Treatment with TKI (upfront in #50%)
Ref
Kim
Kim
Porta
TKI
2009
2010 (asco)
2011
n
Brain RR
Gefitinib or
Erlotinib
23
74%
Gefitinib
23
70%
Erlotinib
17
82%
Extra neural RR
70%
88%
From Chiu et al, Lung Cancer 2005
42-yr old nurse
Gefitinib
7 avril 2011
20 mai 2011
Courtesy of Dr A Augier, Hop Avicenne
LANDSCAPE (phase IIa)
- breast cancer exrpessing HER2 with brain metastases
- n= 45 pts
- previously treated with trastuzumab in 42 pts
Ttt with Lapatinib + Capecitabine.
Cerebral Response rate (≥50% reduction) = 67%
Bachelot et al, ASCO 2011; abstr 509
Robinet et al, 2001
NSCLC
No previous treatment
Brain met
Global PFS
Chemotherapy alone
27% brain RR
Chemotherapy + WBRT 33% brain RR
survival
CT: n=86
CT+RT: n=85
Timing of WBRT
still difficult to define
- no impact in NSCLC
- positive impact in SCLC, especially in a prophylactic setting
- Role of radiosensitivity?
- Role of blood-brain-barrier (BBB) ?
- macroscopic metastases, with disrupted BBB
chemo alone? (with WBRT at relapse +++)
- microsopic metastases, with intact BBB
upfront WBRT ?
Chemotherapy (and delayed WBRT)
Need for randomized trial ++
Chemotherapy + WBRT
Chemotherapy
in a prophylactic setting?
Brain metastasis
Blood-brain-barrier
1ary
tumor
Tumor-Blood
seeding
Brain invasion &
micrometastasis
Brain
metastasis
Selection beyong the BBB
stage IV melanoma, without evidence of CNS metastases
- TMZ
- Dacarbazine
+ Cisplatine + IL2
+ Cisplatine + IL2
Cumulative incidence of central nervous metastases
DTIC
TMZ
n= 74
n= 75
Survival
Other targets
Cancer Sci.
Sci. 2004 Feb;95(2):142
Feb;95(2):142--8.
Increased expression of integrin alpha3beta1 in highly brain metastatic
subclone of a human non-small cell lung cancer cell line.
Yoshimasu T, Sakurai T, Oura S, Hirai I, Tanino H, Kokawa Y, Naito Y, Okamura Y, Ota I, Tani N,
Matsuura N.
Nature, 2009
…..
Brain metastasis
Blood-brain-barrier
invasion
1ary
tumor
seeding
angiogenesis
Retrospective analysis of TARGET (phase III ):
• renal carcinoma without CNS metastases
• second-line treatment with Sorafenib (anti-VEGF, PDGF, Raf)
In summary
- Macroscopic Brain metastases are chemosensitive
Respective place of Chemo/RT to be reconsidered
- Prophylaxis of brain met by chemotherapy/targeted therapy?
(especially in lung cancer, breast cancer, melanoma)
A role for astrocytes ?
BAT
TUMOR
GFAP
Kim et al, Neoplasia, 2011
A role for astrocytes ?
Kim et al, Neoplasia, 2011